Project Summary ? Project 3 Models of the activity changes in the basal ganglia-thalamocortical circuitry in Parkinson's disease have been instrumental for the development of new surgical and pharmacologic antiparkinsonian therapies. However, it has become clear that these models do not fully explain the complex alterations in the patterns of neuronal activity and abnormal network oscillations in the parkinsonian brain. Especially, our knowledge of the anatomical, functional, and pathological changes in the thalamocortical and corticothalamic systems in Parkinson's disease is very limited. In conjunction with the functional studies of projects 1 and 2, and the technical support of Core B, the proposed studies will help us to gain a detailed understanding of the organization and pathology of the synaptic networks through which basal ganglia, thalamic and cortical neurons interact. Our preliminary studies provide strong evidence that the synaptic microcircuits that mediate the communication between the basal ganglia receiving portion of the thalamus and motor cortices display significant pathology in the non-human primate model of Parkinson's disease. At the cortical level, a loss of dendritic spines on projection neurons and a prominent decrease in the thalamic innervation of deep cortical layers was found in M1 of MPTP-treated parkinsonian monkeys. Both findings are strong indicators of pathologic disturbances of thalamocortical communication in parkinsonism. Interestingly, it appears that these changes are particularly prominent in M1, suggesting that the network dysfunction is regionally specific. Combined with recent electrophysiological data showing that the activity of corticospinal, but not corticostriatal, neurons is disrupted in M1 of parkinsonian monkeys, we hypothesize that pathological changes in thalamocortical synaptic connections may differentially affect corticospinal over corticostriatal neurons. Our preliminary data also suggest that the relationships between the thalamus and motor cortices may be impaired by synaptic changes at the thalamic level in parkinsonian monkeys, such that the synaptic connectivity of cortical afferents with GABAergic interneurons and projection neurons is altered. In light of these preliminary findings, we propose a series of morphological, neuropathological, and ultrastructural studies to further assess and quantify the changes in the architecture of the thalamocortical and corticothalamic synaptic networks in normal and MPTP-treated parkinsonian monkeys, as well as in normal and 6-OHDA-treated mice (for comparisons with the studies in primates). The results of these studies will be of critical importance for our understanding of the pathophysiology of parkinsonism, and will aid the interpretation of the functional data obtained in the other projects.